Processing with Cuscuta chinensis Lam. juice mitigates Tripterygium wilfordii Hook.F. toxicity via a multi-mechanistic approach and enhances its anti-rheumatic efficacy

Ethnopharmacological relevance: Tripterygium wilfordii Hook.F. (LGT) is a potent anti-rheumatic herb whose clinical utility is severely limited by multi-organ toxicity, particularly to the reproductive system. Detoxification strategies that preserve efficacy are urgently needed. Proper herb-juice excipient processing, a traditional Chinese medicine detoxification strategy, may mitigate toxicity while enhancing efficacy.

Objective: This study aimed to evaluate whether processing LGT with the juice of Cuscuta chinensis Lam. (TSZ), a kidney-tonifying herb, could reduce toxicity and elucidate the underlying mechanisms.

Materials and methods: The optimal processing protocol was determined by measuring triptolide (TP) content via HPLC. The detoxification effects of TSZ-processed LGT (TL) were assessed in mice after 90-day administration through histopathology and serum biomarkers. Mechanisms were investigated using network pharmacology prediction, Western blotting for G protein-coupled Estrogen receptor (GPER), 16S rDNA Sequencing for gut microbiota, and HPLC for component analysis. Anti-rheumatic efficacy was evaluated in a collagen-induced arthritis (CIA) model.

Results: The results demonstrated that Processing with 20% TSZ juice maximally reduced TP content. TL significantly alleviated LGT-induced reproductive, hepatic, and renal toxicity, reversed testicular GPER overexpression, and restored gut microbiota dysbiosis (e.g., increased Ligilactobacillus). Three TSZ-derived Flavonoids (hyperoside, astragalin, isoquercitrin) were introduced into TL. In the CIA model, medium-dose TL retained anti-rheumatic efficacy comparable to raw LGT, while high-dose TL exhibited superior efficacy, indicating a broadened therapeutic window.

Conclusion: In conclusion, TSZ juice processing effectively attenuates LGT toxicity, potentially mediated by a multi-mechanistic approach involving reduction of TP, introduction of protective Flavonoids, modulation of gut microbiota, and regulation of testicular GPER. Crucially, this processing strategy broadens the therapeutic window of LGT, offering a promising approach for its safer clinical application.